DESCRIPTION: (Applicant's Abstract) Cocaine and amphetamine are powerful psychomotor stimulants and widespread abuse of these drugs creates a major problem in the society. Understanding the molecular mechanisms underlying the behavioral and neuroplastic changes caused by cocaine and amphetamine is crucial for developing methods of the prevention and treatment of drug abuse. It has been demonstrated that the acute actions of these psychostimulants depend on the potentiation of dopamine neurotransmission in the mesolimbic dopamine pathway, particularly through the D1 dopamine receptors. However, little is known regarding the intracellular events mediating the effects of these psychostimulants. Immediate early gene c-fos encodes a transcription factor and is induced through the D1 dopamine receptors by both cocaine and amphetamine. Our hypothesis is that c-fos is necessary in mediating both the locomotor stimulating and positive reinforcing effects of cocaine and amphetamine, and in AP-1 transcription complex formation in response to acute cocaine treatments. We propose to use the conditional gene targeting technology and generate mice with forebrain mutation of c-fos. We propose to test the above hypothesis in these mutant mice using behavioral, biochemical and histological methods. The successful completion of the proposed project will allow us to determine the role of c-fos in mediating the acute actions of psychostimulants and provide basis for investigating its role in the chronic effects of these drugs, and for finding possible target genes involved in drug addiction in the future.